Study uncovers 3,000 "genomic hotspots" in embryonic stem cells

Published: Saturday, June 14, 2008, 12:47 [IST]

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Washington, June 14 : Researchers at the Genome Institute of Singapore (GIS) and the National University of Singapore (NUS) have made a chart showing over 3,000 "genomic hotspots" of essential protein "switches", also known as transcription factors, which are critical for maintaining the embryonic stem (ES) cell state.

Unveiling their chart in the journal Cell, the researchers revealed that they used advanced high throughput sequencing technology during the study.

The researchers say that their findings may help improve understanding of the unique properties of stem cells that enable them to maintain their intriguing ability to grow and differentiate to virtually any cell type.

"This is the first time such a large scale study has been conducted in Singapore and obtaining such groundbreaking results has caused much excitement. This blueprint that we obtained is like a treasure map, pointing us to specific sites where we can further study how these switches interact within the cell. Hopefully, this will eventually allow us unlock the secrets of stem cells," said Dr. Wei Chia Lin, senior group leader at GIS.

Dr. Ng Huck Hui, also a Senior Group Leader at GIS, added: "We think that these 'stemness' hotspots are the most critical points in the genetic blueprint of ES cells. By targeting these hotspots, we may be able to reconnect the wiring in non-stem cells and jump-start the stem cell program in them. This can potentially create an inexhaustible source of clinically useful cells for regenerative medicine or cell based therapies in the future."

The researchers say that they have started further investigating into this research area.

"Using cutting edge sequencing technology, scientists from the GIS and NUS have identified hotspots in embryonic stem cells. These are important hubs of the genome of embryonic stem cells. This piece of work illustrates how scientists from different disciplines and across institutions can come together to define fundamental features of these intriguing cells," said Prof. Lee Eng Hin, Executive Director of A*STAR's Biomedical Research Council.

Dr. Alan Colman, Executive Director of Singapore's Stem Cell Consortium, said: "In this new paper in Cell, the team at the GIS continues their remarkable progress in defining the precise DNA sequences to which an important group of 13 transcriptional factors bind in mouse embryonic stem cells."

He added: "This particular group of factors is responsible for maintaining the self renewal and pluripotency of the embryonic stem cells. The team shows that many of the factors which bind to the same gene regions ('hotspots') and their work provide a working model of the transcriptional networks at play within the cells, and how these intracellular networks are linked to events that can be influenced by external stimuli."

During the course of study, the researchers performed genome-wide mapping of the in vivo binding sites for 13 sequence-specific transcription factors in ES cells, which play different roles in self-renewal, pluripotency, reprogramming and chromatin insulation.

They said that the study unveiled twos major modes of binding that give rise to transcription factor co- localization hotspots.

The Nanog/Oct4/Sox2 centric hotspots are commonly co-bound by Smad1 and STAT3, and they represent points of integration for the intrinsic and external signalling pathways, added the researchers.

According to the research team, the combinational wiring of transcription factors may be helpful in deciphering the code behind gene expression program in ES cells.